Optimizing the Personalized Care for the Management of Rectal Cancer: A Consensus Statement

Colorectal cancer is the third most common cancer in Turkey. The current guidelines do not provide sufficient information to cover all aspects of the management of rectal cancer. Although treatment has been standardized in terms of the basic principles of neoadjuvant, surgical, and adjuvant therapy, uncertainties in the management of rectal cancer may lead to significant differences in clinical practice. In order to clarify these uncertainties, a consensus program was constructed with the participation of the physicians from the Acıbadem Mehmet Ali Aydınlar and Koç Universities. This program included the physicians from the departments of general surgery, gastroenterology, pathology, radiology, nuclear medicine, medical oncology, radiation oncology, and medical genetics. The gray zones in the management of rectal cancer were determined by reviewing the evidence-based data and current guidelines before the meeting. Topics to be discussed consisted of diagnosis, staging, surgical treatment for the primary disease, use of neoadjuvant and adjuvant treatment, management of recurrent disease, screening, follow-up, and genetic counseling. All those topics were discussed under supervision of a presenter and a chair with active participation of related physicians. The consensus text was structured by centralizing the decisions based on the existing data.


INTRODUCTION
Colorectal cancer (CRC) is the third most common cancer in Turkey. 1 Management of rectal cancer consists of a combination of neoadjuvant therapy, surgery, and adjuvant treatment. However, the current guidelines do not cover all aspects of management of rectal cancer, especially for the diagnosis of rectal cancer, defining organ preservation strategies, selection of proper neoadjuvant modalities, surgical treatment for the primary disease, the role of adjuvant therapy, management of recurrent disease, screening, follow-up, and genetic counseling. Thus, a lack of standardization may lead to significant differences in clinical practice. This consensus program aimed to establish feasible, logical, measurable, and collective solutions to challenges that our participant physicians from 2 leading academic institutions face during the management of rectal cancer. Secondly, we aimed to emphasize that multi-disciplinary tumor boards (MDTB) should be mandated before any management decision is made regarding the treatment of the rectal cancer.

MATERIALS AND METHODS
One hundred twenty-seven physicians from the departments of gastroenterology, general surgery, genetics, medical oncology, nuclear medicine, radiation oncology, radiology, and pathology of Acıbadem Mehmet Ali Aydınlar and Koç Universities organized a consensus program to focus on the management of rectal cancer. This consensus program included management of rectal adenocarcinoma solely. Other histologic types of rectal cancers were excluded. A board committee was assigned to define the gray zones in the management of rectal cancer by reviewing the evidence-based data and current guidelines. This committee consisted of at least 1 representative from each department. Topics regarding diagnosis, staging, surgical treatment of primary disease, use of neoadjuvant and adjuvant therapy, management of recurrent disease, screening, follow-up, and genetic counseling were determined by the committee for discussion. These topics were discussed, voted, and ratified statement by statement under the supervision of a presenter and a chair along with the participation of a large group of physicians. Unanimously agreed statements were included in the consensus paper. Eighth version American Joint Committee on Cancer Union for International Cancer Contr ol/Tu mor-N ode-M etast asis (AJCC-UICC/TNM) classification was used for staging.

Presentation, Diagnosis, and Local Management for Primary Disease
The reported incidence of CRC in Turkey is 13-22 cases/ 100 000 population per year and is predicted to increase. Approximately, 30% of colorectal tumors originate from the rectum. Clinical investigations have shown that epidemiology, etiology, and risk factors of rectal cancer differ from that of colon cancer. [2][3][4]

Diagnosis of Rectal Carcinoma
Rectal cancer is categorized as low (up to 5 cm from the anal verge), middle (between 5 and 10 cm from the anal verge), or high (between 10 up to 15 cm from the anal verge) according to its location. Diagnosis of rectal cancer is established by colonoscopy and biopsy. 5 The lower rectum, anal canal, and prostate gland can be examined by digital rectal examination (DRE). However, DRE has a low sensitivity as a screening evaluation since it may be associated with high false-negative results. 6 Highresolution optical methods such as narrow-band imaging, laser confocal endoscopy, or chromoendoscopic methods using dye solutions can be used to identify high-risk, flat premalignant lesions or early-stage carcinomas. Flat or depressed lesions carry a higher risk of in situ or invasive carcinoma. A complete colonoscopy should be performed to rule out synchronous tumors, as well as polyps at the rest of the colon, after finding a suspicious lesion.

Use of Rigid Rectoscopy
The current gold standard for the detection of colorectal cancer is a flexible colonoscopy. A rigid rectoscopy may have the advantage of taking deeper and larger biopsies. 7 Use of an Endoscopic Ruler The experience of an endoscopist is the most important determinant for the accurate determination of lesion size. 8 The use of an endoscopic ruler may enable endoscopists to measure and describe rectal cancer more accurately.

Role of Carcinoembryonic Antigen in a Clinical Setting
Carcinoembryonic antigen (CEA) allows effective disease monitoring of CRC during adjuvant treatment and postoperative follow-up. The European Group on Tumor Markers, European Society of Medical Oncology, and American Society of Clinical Oncology guidelines do not recommend CEA as a screening test. Elevated CEA concentrations in patients with stage II and III CRC were found to be associated with aggressive behavior of cancer. From a prognostic point of view, it is reasonable to monitor CEA levels after diagnosis of rectal cancer for detection of recurrences. [9][10][11] IMAGING AND PREOPERATIVE STAGING Standard Imaging Modality A magnetic resonance imaging (MRI) of the pelvis and a thoracoabdominal computed tomography (CT) are the standard imaging modality for staging rectal cancer. High-resolution pelvic MRI plays a critical role in surgical decision-making since it provides detailed images of mesorectal fascia and its contents. Magnetic resonance imaging has a high specificity (92%) for negative clear resection margin estimation. 12 It is superior from other modalities in detecting extramural vascular invasion (EMVI), determining T sub-stages, and determining the distance of tumor to mesorectal fascia. Thus, preoperative complete resection margin can be evaluated accurately, and patients can be risk-stratified via MRI. 13 Magnetic resonance imaging has higher sensitivity and accuracy than endoscopic ultrasonography (EUS) in nodal staging. 14 Endoscopic ultrasonography is more specific than MRI in the evaluation of muscularis propria invasion; therefore, it should be performed for staging of T1-T2 tumors, prior to planning of local excision. 15,16 In obstructing cancers, the endoscopic ultrasound scope may not be able to traverse the malignant stricture and therefore may not accurately evaluate the depth of tumor invasion. Therefore, the accuracy of EUS for the staging of T4 tumors ranges between 44% and 50%. 17 Rather than choosing one against the other, MRI and EUS can be used together as needed for defining the stage of cancer more accurately. 14, 17 Studies on the outcome of dynamic contrast-enhanced (DCE)-MRI after primary and neoadjuvant therapy are inconclusive. 18 Magnetic Resonance Imaging Criteria for Pathologic Perirectal Lymph Nodes Sensitivity of MRI for nodal staging in rectal cancer was found to be only 66%-77% and specificity was 71%-76% in meta-analyses. 16,19,20 Although the perirectal lymph node involvement is an important factor in the likelihood of metastatic disease, its overall positive predictive value is low. 21 Magnetic resonance imaging may not identify nodal micro-metastases when the perirectal lymph nodes are smaller than 5 mm. 22 Approximately, 25% of the lymph nodes were shown to be over-staged. 16 If any perirectal lymph node is 9 mm or wider on the short axis, it should be reported as suspicious. 15 Irregular contour, round shape, and heterogeneous signal content are the morphological MRI criteria for metastatic perirectal lymph nodes regardless of their size. 15,22,23 Basic Parameters of an Magnetic Resonance Imaging Report for Local Staging The report of a high-resolution rectal MRI should be comprehensive during initial staging and after neoadjuvant treatment. [24][25][26][27] Distance between the lowest tumor margin and the anal verge should be included in the report. The size and the circumferential location of the tumor within the wall ought to be described in a clockwise manner. 28 Describing the tumor location in relation to the anterior peritoneal reflection is important. 28 Description of T-stage, especially 3 sub-stages to determine the depth of tumor invasion, the nearest distance to mesorectal fascia, and relations with the anal sphincter and levator ani muscles are important prognostic factors. 24 Rectal MRI reports should include the location and morphology of suspicious nodes, as well as EMVI status. 19,29,30 The report should be finalized with a cTNM.

SPECIFIC CONSIDERATIONS AT THE TIME OF DIAGNOSIS AND STAGING Definition of the Upper Rectum
In order to determine the treatment strategy, differentiation between the distal sigmoid colon and the upper rectal tumor is important. 31 There is considerable sex and racial variation in the length of rectal and anal canal. Radiologically, the definition of the upper border of rectum varies between S1 and S3 vertebral levels. 32 The rectosigmoid junction is surgically determined by loss of taenia coli, the onset of peritoneal reflection, and sacral promontory. 33,34 Endoscopic and radiologic (MRI) definition of the upper border of rectum varies between 12 and 15 cm from the anal verge. [35][36][37][38][39] However, those definitions do not correlate in a considerable amount of patients. In a study of 128 patients with tumor level determination of sigmoid and rectal cancers, the concordance between endoscopic and radiologic measurement was found to be approximately 80%, and the overall accuracy was 87.5% for endoscopy and 90.5% for imaging. 40 In case of any discordance in determining the anatomic borders of the rectum, a joint decision should be made to determine management strategy. 41

Management of Malignant Polyps
Any polypoid lesion (pedunculated, sessile, or flat) noted during colonoscopy should be completely resected. Pedunculated lesions are removed by snare polypectomy technique. Local recurrence and lymph node metastasis of completely resected pedunculated polyps confined to the superficial submucosa without any unfavorable histopathologic findings are negligible. 42,43 Therefore, surgery can be omitted in these cases. For pedunculated polyps with unfavorable histological features (<1 mm cancer-free margin, poor histological differentiation, vascular or lymphatic invasion), invading the submucosa of the bowel wall below the stalk of a polyp, or extending through the submucosa into the deeper wall surgery is recommended. 44,45 Endoscopic removal of laterally spreading flat lesions may require more advanced resection techniques.

PRINCIPLES OF LOCAL EXCISION FOR RECTAL CANCER TREATMENT
While endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are suggested as effective and safe alternatives to surgery for patients with superficial and early neoplastic lesions of the rectum in selected cases, those procedures may result with positive margin, because during the ESD procedure, the plane for the dissection is mostly between the mucosa and submucosa. [45][46][47][48] Difficulty to elevate the lesion with submucosal injection may be an indicator of submucosal tumor invasion and precludes endoscopic resection. It is recommended to obtain the lesion in a single piece for an adequate histopathologic evaluation. Transanal endoscopic surgery (TES) [transanal endoscopic microsurgery (TEM) and a transanal minimally invasive surgery (TAMIS)] can be used for local excision of rectal neoplasms. In patients with polyps having malignant features according to the endoscopic classifications, a proper clinical staging should be performed before procedure. There is no clear evidence for the full thickness re-excision of the ESD/ EMR scar in remnant pT1 lesions.
A diagnostic colonoscopy should not be converted to an advanced endoscopic intervention for treating an early rectal cancer if informed consent is not taken prior to the procedure. A follow-up colonoscopy is recommended in 2-6 months after complete endoscopic removal of a rectal neoplasm. 40,49 If the histopathologic evaluation shows malignant features with undetermined resection margin invasion, surgery should be considered. 50 Since a lesion with submucosal invasion has a risk of lymph node metastasis ranging from 6% to 12%, surgical resection should be considered for endoscopically resected lesions with submucosal invasion. [51][52][53] Accurate histopathologic evaluation of a locally resected specimen is crucial to determine lymph node metastasis risk. The risk of lymph node metastasis of rectal cancer is summarized in Table 1. 54,55 As an alternative to radical surgery, a transanal local excision is a favorable option for cT1(sm1)N0M0 rectal cancer without high-grade differentiation or lymphovascular invasion (LVI). 56 The specimen should be handled cautiously for accurate histopathologic evaluation (depth of invasion, surgical margins, LVI, and differentiation) after transanal local excision. Radical surgery should be performed for a locally excised lesion with a final pathology reporting pT1sm2 disease. 35

Evaluation of Proximal Colon and Staging in the Setting of Obstructive Rectal Tumors
About 3.5% of the CRCs are synchronous. 57 Proximal colon should be assessed with full colonoscopy and abdominopelvic CT with oral and intravenous (IV) contrast at the time of diagnosis. A completely obstructing rectal tumor may not allow a full colonoscopic evaluation to detect possible synchronous tumors. 58 In such conditions, post-surgical colonoscopic evaluation within 3-6 months is reasonable. 17,35,59 There are alternative strategies for synchronous tumor detection for patients requiring emergent surgery. 58 Preoperatively, abdominal CT with contrast can be performed quickly for diagnosis, and chest CT may be added for staging. 60,61 In case of incomplete obstruction, CT colonography with rectal air or water is an option. 62-64 In patients with proven metastatic and obstructive disease, fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) (FDG PET/CT) can be considered to detect other possible sites of metastases. Intraoperative colonoscopy is useful to determine the extent of surgical resection. 58

Imaging Choice of Peritoneal Metastases in Rectal Cancer
Magnetic resonance imaging with diffusion-weighted imaging (DWI) was found to be more accurate (91%) than CT (75%) and FDG PET/CT (71%) for peritoneal staging and to improve the quality of mesenteric/ serosal metastatic spread assessment. 65 Sensitivity of CT for nodules less than 5 mm was reported as only 11%. 66 Average sensitivity of MRI for depicting peritoneal implants of all sizes was 84%, compared to 54% for CT, and sensitivity of gadolinium-enhanced MRI for tumors less than 1 cm was 85%-90%, compared to 22%-33% for CT. 67,68 Accuracy of MRI (0.88) was found to be higher than CT (0.63) in determining the peritoneal cancer index (PCI) for the planning of cytoreductive surgery. 69 Diffusion-weighted imaging and delayed gadolinium-enhanced MRI were reported as the most accurate imaging methods for detecting peritoneal tumors. 70 It is important to recognize that distal mesorectal spread often extends further than intramural spread, with deposits found up to 3-4 cm distal to primary cancer. For the middle and lower third of the rectal cancers where TME is performed, the distal margin is recommended to be at least 1 cm. 85,86 It has been reported that PME was a less complex procedure with a lower anastomotic leakage rate compared to TME. 87 The morbidity rate of TME seems high with an increased risk of anastomotic leakage with low anastomoses. Up to 17% of anastomotic leakage with 11% of postoperative peritonitis has been reported after TME. 88 Therefore, the routine use of intestinal diversion has been advocated with TME. 89 Intersphincteric TME can be performed for the management of the lower third of rectal cancer close to the dentate line where the anastomosis is performed at the anorectal ring or dentate level. The decision should be given preoperatively on whether to perform transanal hand-sewn anastomosis or double-stapled anastomosis. 94 Abdominoperineal resection (APR) should be performed after neoadjuvant treatment in patients with distal rectal tumors invading levator muscles and external anal sphincters.
During the classical APR, surgeons preserve the levator ani, leading to dissection very close to the tumor and creating "Morson's waist" defect. Cylindrical APR allows achieving a monobloc excision of the portion of levator muscles that are not otherwise removed during classic APR. Cylindrical APR is a better method of preventing CRM (+), particularly at the level of levator muscles. 13 110,111 Selfexpanding metal stent is not preferred as a long-term treatment due to stent migration and stent-related perforation. 112 Self-expanding metal stent placement is not recommended for patients with extraperitoneal rectal cancer. Stenting is also contraindicated in patients with potentially curable rectal cancer.

Basics of Pathologic Analyses for the Treatment of Rectal Cancer
Histopathologic examination is the gold standard for the diagnosis of rectal cancer. Obtaining the right amount of tumor tissue during endoscopy is essential for the accurate diagnosis. Although current guidelines do not specifically state the number of biopsies required, several studies demonstrated that the diagnostic sensitivity increases significantly with the increased number of biopsies taken. 113

Reflex Testing of Caudal-Related Homeobox Transcription Factor 2
In the literature, IHC loss of caudal-related homeobox transcription factor 2 (CDX2) in CRCs is claimed to be associated with aggressive histological features, including poor differentiation, lymph node metastasis, and lymphovascular and perineural invasion, as well as worse disease-free survival (DFS) 118 and may benefit from adjuvant chemotherapy. 130 Caudal-related homeobox transcription factor 2 cannot be used as independent prognostic marker; however, it is correlated with MMR status and BRAF mutation. 119 Caudal-related homeobox transcription factor 2 immunostaining is often heterogeneous and scoring with CDX2 is not well established.
Reflex testing of CDX2 immunostaining on rectal tumor specimens is optional due to controversies regarding its prognostic significance in the literature. However, it can be carried out for academic purposes.

Pathological Evaluation of Local Excision Specimens
Minimally invasive endoscopic methods are increasingly used for en-bloc resection of colorectal lesions including adenomas and early carcinomas for selected patients. These specimens should be carefully handled for gross photography and margin orientation. Specimens should be sent en-bloc for histologic examination. Histological parameters that should be included in the pathology report are similar to malignant polyps.

Pathological Evaluation of Radical Resection Specimens
Appropriate handling and thorough histopathological examination of surgical specimens for rectal cancers (low AR and APR) are essential to assess the quality of the surgical treatment, as well as to predict the outcome of the patient and to determine further treatment options. Protocols of the American Joint Committee on Cancer (AJCC) and College of American Pathologists (CAP) are widely acknowledged systems to evaluate these specimens with regard to pathological staging and reporting.
Neoadjuvant chemoradiation therapy in locally advanced rectal cancer has been proven to result in significant tumor response and downstaging. A modified Ryan scheme is recommended as a standard scoring system by the CAP to report tumor response.
Although it is not included in the CAP and AJCC protocols, several studies have shown the prognostic significance of subdividing T3 rectal tumors according to the microscopic depth of perirectal fat invasion. 122,123 PAN-RAS testing Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies have been the main targeted therapies for metastatic CRCs that require knowledge of the mutational status of genes in the pathway as predictive biomarkers of response to these therapies. Epidermal growth factor receptor signaling pathways involving KRAS, NRAS, BRAF, PIK3CA, and PTEN affect response of CRC to anti-EGFR antibody therapies. According to several studies and guidelines for CAP/ASCO/AMP, KRAS and NRAS (PANRAS) mutation analysis covering second, third, and fourth exons of these genes need to be performed before starting anti-EGFR therapy.  134 This large randomized trial showed that local control and toxicity were improved in the neoadjuvant arm. Short-course RT has also proven to improve local control, even in patients to be operated with TME in the Dutch trial. 135 Preoperative short-course RT and long-course CRT were compared in the TROG trial and resulted in similar oncological outcomes. 136 There was a non-significant local recurrence difference in distal tumors in favor of long-course CRT (12% vs 3%, P = .21). In a randomized study with unresectable cancers, longcourse CRT was superior to short-course RT in terms of R0 resection, pathologic complete response (pCR) (16% vs 7%), local control (82% vs 67%), DFS, and cancer-specific survival rates. 137 Neoadjuvant treatment may be omitted in selected patients with T3N0, CRM−, and proximal rectal cancers who are thoroughly staged with MRI and to be operated with TME by an experienced team. However, sensitivity of radiological methods still cannot provide a precise prediction for lymph node metastases. Besides, unselected patients treated with preoperative short-course RT had a lower local recurrence compared to selectively treated patients with postoperative CRT if they had circumferential margins of £1 mm (4.4% vs 10.6%) in a large randomized trial.
Early (within 1-2 weeks) or delayed surgery may be performed after short-course RT. In the initial studies with short-course RT, surgery was performed within 1-2 weeks after RT. Following trials used a delayed surgery approach (5-13 weeks after RT) in order to increase the tumor response rate. A systematic review analyzed 16 studies, in which it was shown that a lower rate of severe acute postradiation toxicity was observed in the immediate-surgery group. 138 However, this benefit was counterbalanced by the increase in minor postoperative complications. When the surgery was delayed, the pCR rate was about 10% higher, but R0 resection and sphincter preservation rates were similar. A pCR of over 20% was recorded after shortcourse RT and consolidation chemotherapy followed by delayed surgery. Stockholm III trial randomly tested immediate surgery as a standard approach against delayed surgery (4-8 weeks)

Type of Concurrent Chemotherapy Regimen
Both infusional 5-fluorouracil (5-FU) and capecitabine are acceptable chemotherapy regimens concurrently administered with RT. Although early trials have mainly utilized bolus 5-FU during the first and last weeks of RT, concerns of toxicity have caused the elimination of routine bolus 5-FU administration. An early trial comparing adjuvant bolus and infusional 5-FU during pelvic RT has demonstrated superior OS rates for infusional chemotherapy. 143 However, another trial testing bolus and infusional 5-FU with concomitant radiation in the postoperative setting has yielded similar relapse-free survival and OS outcomes, with the expense of more common hematologic toxicity in the bolus 5-FU arm. 144 Non-inferiority of capecitabine has been demonstrated in a phase III study, and local relapse and OS rates have been similar, although distant metastases were less common with capecitabine. 145 Both infusional 5-FU and capecitabine can be used concomitantly with RT by considering their toxicity profiles.
Administration of oxaliplatin concomitantly with RT has provided a modest increase in pCR rates with clearly increased toxicity such as grade 3-4 leukopenia, diarrhea, skin toxicity, and radiation proctitis. 146-151 There has been no DFS advantage with the addition of oxaliplatin during RT except for the German CAO/ARO/AIO-04 trial. 152 Thus, oxaliplatin is not recommended concomitantly during RT.
Infusional 5-FU and capecitabine can be administered concomitantly with RT. The addition of oxaliplatin to infusional 5-FU or capecitabine is not recommended due to lack of survival benefit and increased toxicity.

Total Neoadjuvant Therapy
Earlier delivery of full-dose systemic chemotherapy has the theoretical capacity to eradicate micrometastatic disease and decrease the risk of disease progression during treatment. Moreover, total neoadjuvant therapy (TNT) can provide an opportunity to select patients with clinical complete response (cCR) to be considered for nonoperative management (NOM). Yet, there is no phase III randomized trial comparing the standard CRT approach with TNT, and attempts to increase pCR rates have not always resulted in improved disease-related outcomes. 153 Given the lack of strong evidence for TNT strategy, this approach still can be suggested for patients with middle or distal rectal cT4 and/or N2 tumors or those with CRM (+) T3 tumors after discussion in MDTB. Mainly, 2 pragmatic approaches have been tested to optimize the delivery of trimodality therapy: incorporation of systemic therapy before or after conventional neoadjuvant CRT. The number and type of induction chemotherapy before CRT has been variable in different studies. Induction chemotherapies have mainly included oxaliplatin either as FOLFOX or XELOX and the duration of induction chemotherapy has changed between 3 and12 weeks. 154-159 A recent phase III trial (PRODIGE 23) has utilized the mFOLFIRINOX regimen before long-course CRT in comparison to standard long-course CRT followed by surgery and adjuvant chemotherapy. The experimental arm has yielded significantly higher rates of pCR (27.5% vs 11.5 %), DFS, and metastases-free survival. Overall survival data are not mature yet (332). Administration of chemotherapy after CRT has also been tested in several small-scale studies. 160-163 A multi-institutional phase II randomized trial has demonstrated that increased pCR rates correlated with the number of chemotherapy cycles administered after the CRT until surgery. 164 The most common RT regimen utilized in TNT studies has been long-course CRT. However, a phase III trial has compared the efficacy of short-course RT followed by 3 cycles of FOLFOX regimen with standard CRT protocol and interestingly has yielded superior OS outcomes without difference in DFS or local control rates. Administration of systemic chemotherapy during the "resting period" between CRT and surgery has been assessed with different strategies but none has shown survival benefit despite an increase in cCR or pCR rates. 159,164-166 Although the method for evaluating response has differed across trials, serial digital rectal examination, rigid proctoscopy, abdominopelvic CT/MRI, and serum CEA levels can be performed before CRT when feasible or after CRT completion and at 2-3 months intervals depending on the interval between surgery and the initiation of TNT. 167 Yet, using a variety of radiologic modalities to assess tumor regression and predicting pCR remains an area of active research due to high falsenegative rates with either anatomic or functional (FDG PET/CT) imaging techniques. [168][169][170] Given the lack of strong evidence for benefit of TNT approach, it can be considered for mid or low rectal cT4 and/or N2 tumors or cT3 tumors with high risk for CRM-positivity based on MDTB decision. Oxaliplatinbased chemotherapy, either as FOLFOX or XELOX, can be administered before or after CRT. Both induction chemotherapy followed by CRT or CRT followed by systemic chemotherapy are acceptable strategies. Completion of the planned chemotherapy during the neoadjuvant period (a total of 6 months) can be preferred due to increased compliance. Response to treatment can be done every 2 months preferentially with the tools used initially during clinical staging. Surgery can be performed 2-3 weeks after the last chemotherapy cycle or 6-8 weeks after the last RT fraction for long-course RT.

Adjuvant Chemotherapy
The evidence regarding the efficacy of adjuvant chemotherapy/CRT for patients who have not received neoadjuvant CRT has relied mainly on early studies that utilized chemotherapy agents inferior to modern standards and a Cochrane meta-analysis which included early studies performed with 5-FU-based therapies. Response to neoadjuvant therapy has not consistently been a useful tool for the selection of patients who would benefit from adjuvant chemotherapy. Unplanned subgroup analysis of some trials and nomograms has pointed at a DFS benefit for ypT3-4 or ypN2 disease (non-responders) whereas there are 2 retrospective cohort studies pointing at survival advantage with adjuvant chemotherapy for patients achieving pCR after neoadjuvant CRT. 152,180,181 Given the lack of prospective data, recommendations should be made on individual patient basis in MDTB taking the patient-related factors into consideration.
Response to neoadjuvant therapy is not a useful tool for predicting benefit from adjuvant chemotherapy either. Each case should be discussed in MDTB, and the patient should be informed about the risks and benefits of the suggested treatment. Addition of oxaliplatin in the adjuvant setting after neoadjuvant chemotherapy may provide DFS benefit for clinical/pathologic T3-T4 and/or node-positive disease.
Currently, there are no trials addressing the optimal duration of adjuvant chemotherapy for rectal cancer. Since the data are not conclusive, we recommend 4 months of adjuvant chemotherapy when neoadjuvant CRT is administered.

SPECIFIC CONSIDERATIONS When to Perform Surgery After Neoadjuvant Treatment
Sun et al 182 reviewed the National Cancer Database for optimal surgical timing after neoadjuvant therapy. Eight weeks appear to be the critical threshold for optimal response. While optimal surgical timing has been previously reported to be 6-8 weeks after long-course neoadjuvant therapy and 1 week after the short course, the optimal duration of interval after CRT has been controversial.
OSTriCh 183 group also reviewed the National Cancer Database and found that a nCRT surgery interval time of >8 weeks results in increased odds of pCR, with no evidence of associated increased surgical complications compared with an interval of 6-8 weeks. These data support the implementation of lengthened interval after nCRT to increase the chances of obtaining a pathologic complete response. In the latest analysis of 11 760 patients, the optimum interval for complete resection and downstaging was concluded as 8 weeks. 182 Another study from Korea 184 reported the optimal timing for curative surgery in rectal cancer when tumor response is maximal as after 7 weeks and before 10 weeks following preoperative nCRT. GRECCAR-6 randomized stage II-III patients treated with CRT into 2 groups according to the timing of the surgery as 7 or 11 weeks after completion of the CRT. Pathologic complete response was similar between groups (15% vs 17.4%), but the morbidity and complete resection rates were worse at 11 weeks. 155 therapy. For short-course therapy, surgery can be considered at 3-7 days or 4-8 weeks.
Another meta-analysis has recently demonstrated that pCR rates are significantly increased in patients with locally advanced rectal cancer after a waiting interval of >8 weeks after nCRT and surgery compared to a waiting interval of <8 weeks. There were no significant differences in OS, DFS, operative time, or incidence of local recurrence, postoperative complications, or sphincter-preserving surgery. 186 We currently recommend optimum interval time as 6-8 weeks 191 While it is optional in some guidelines, 27,192 the value of restaging MRI has been pointed out by many authors. 26,193 The accuracy of MRI decreases after nCRT due to fibrosis, wall thickening, and inflammatory changes. 194 The reported accuracy rates of post-CRT MRI for T staging and N staging were 48% and 63.8%, respectively. 194 In a large meta-analysis, it was reported that the mean sensitivity rate of MRI for T staging increased from 50.4% to 73.6% with the addition of DWI after CRT. 195 Although abdominal/pelvic CT after neoadjuvant therapy has been shown to identify resectable liver metastases in only 2.2% of patients (95% CI, 0.8%-5.1%), 196  The CLOSE-IT study is looking for optimal ileostomy closure timing, and the study is still recruiting patients. 200 At the moment, there is no strict rule for ileostomy closure timing. In our practice, delayed closure is routinely performed.

Nonoperative Management of Rectal Cancer
A watch-and-wait approach for patients with a cCR to neoadjuvant chemoradiation could avoid the morbidity of conventional surgery for rectal cancer. However, the safety of this approach is unclear. 201 In 2004, Habr-Gama et al 157 compared the outcomes of 71 patients who were observed without surgery following complete clinical response who had incomplete clinical responses but complete pathologic responses post TME.
The OS and DSF rates at 5 years were 100% and 92%, respectively, in the nonoperative group compared to 88% and 83%, respectively, in the resected group. However, other studies did not achieve such impressive results, and many clinicians were skeptical of this approach. 202 Several systematic reviews have been published on the nonoperative approach. 201,[203][204][205] They all show that the approach is likely safe with the use of resection in patients with tumor regrowth, but that the data are very limited.
Despite the impressive results of prospective trials, many still believe that longer follow-up, larger sample sizes, and additional careful observational studies are needed before patients with cCR are routinely managed by the watchand-wait approach. 205 NCCN guideline panel believes that NOM and the proper approach for patients who are unfit for surgery and/or desire a stoma-free treatment may be considered in centers with experienced multidisciplinary teams after a careful discussion of the patients' risk tolerance.

Metastatic and Recurrent Disease
Patients with metastatic rectal cancer can present in 3 clinical scenarios: upfront resectable, potentially resectable, and nonresectable disease.
The majority of the patients with metastatic rectal cancer (70%) are nonresectable at presentation. 207 Thus, the goal of the treatment is to prolong survival and increase the quality of life. A subset of patients with metastatic rectal cancer (30%) present with an oligometastatic disease in the liver and/or lung, local recurrence after definitive treatment, or limited intraabdominal disease. 207 In these patients, there is a chance for curative surgical treatment. One-third of these patients are upfront resectable and two-thirds of them are potentially resectable after conversion therapy with systemic and/or local treatments. The probability of downstaging a patient with unresectable disease to resectable disease is 10%-20%.
In large series, it was seen that 77% of the patients with metastatic colorectal cancer had unresectable liver metastases at the time of diagnosis, 207 and 13% of the patients with unresectable liver metastases were significantly downstaged with conversion therapies. This means that 33% of metastatic CRC with liver metastases can be resected up front or after conversion therapy. 207 The survival of patients who are resected following conversion chemotherapy is similar to that of patients whose diseases are resectable at diagnosis. 208 If both the primary tumor and metastases are resectable at diagnosis, one approach is to start with shortcourse pelvic RT followed by synchronous resection of the primary and metastatic disease. However, there are other approaches to integrate systemic chemotherapy into preoperative treatment, rather than postponing to the postoperative period. 35,59 In all of these approaches, pelvic RT should be completed before surgery. Shortcourse RT is preferred over long-course CRT. 35 The alternative approaches are as follows: (i) initial chemotherapy followed by short-course RT and surgery, and (ii) short-course RT followed by chemotherapy followed by surgery. 35 209 Therefore, in rectal cancer with synchronous potentially resectable liver metastases, systemic treatment with the highest response rate should be selected depending on the molecular characteristics of the tumor.
The benefit of pelvic RT in these patients is unclear as there are no randomized trials. In 2 retrospective studies, patients who did or did not receive RT had similar rates of local and OS. 210,211 The recurrences usually involved distant sites rather than locoregional recurrences, even in patients treated without pelvic RT. 211 Although, the benefit of RT on OS has not been established, prevention of local recurrence through the addition of pelvic RT is an important goal considering the morbidity of locoregional recurrence. Thus, the efforts should focus on achieving margin-negative resections at the earliest moment, while not allowing delays in systemic treatment and avoiding locoregional recurrences. Although consensus guideline from the NCCN suggests both short-course RT and longcourse CRT, we prefer short-course RT which is also supported by the ESMO. 35,59 One of the following strategies is acceptable in rectal cancer with potentially resectable liver metastases: (i) initial chemotherapy followed by RT then resection (synchronous or staged), and (ii) initial RT followed by chemotherapy and then resection. It is recommended to be determined by MDTB in an individual manner.

Role of Intraoperative Ultrasonography
Intraoperative ultrasound (IOUS) is recommended as a standard modality due to its superiorities for detecting unrecognized liver metastases with conventional imaging modalities. 212,213 Intraoperative ultrasound is a useful tool to confirm tumor location during the operative period, identify the resection margins, and facilitate parenchymal transection. 214 In a systematic review, IOUS and laparoscopic ultrasonography (LUS) performance for detecting synchronous liver metastases in patients undergoing primary colorectal carcinoma surgery was evaluated. It was reported that the detection rate of additional liver metastasis was ranging between 32% and 57% in patients who had IOUS and 2%-13% in patients who had LUS compared to preoperative contrast-enhanced CT and/ or MRI. 215 Therefore, we recommend an evaluation with IOUS in patients undergoing surgery for metastatic liver disease, regardless of the type of surgery (open or laparoscopic).

Assessment of Resectability and Principles of Surgery for Hepatic Metastases
The term "resectability" means more than just "feasibility of surgical removal" in practice; in fact, it also covers oncological reasoning and patient selection. From a technical perspective, 2 criteria must be fulfilled to accept liver metastases as "resectable": (1) R 0 -resection should be possible, and (2) future liver remnant should be sufficient. If one of these criteria is not fulfilled, then the term "potentially (borderline) resectable" is used. And if none of these criteria is fulfilled, then liver metastases are considered "unresectable". 35,59,216,217 A multidisciplinary meeting discussion, in which an experienced hepatobiliary surgery team is involved, is the best way to assess resectability by all means and determine an individualized treatment algorithm for each patient. The assessment of resectability is of paramount importance because the major determinant of survival is metastatic disease in stage IV rectal cancer, and surgical resection is the only potential curative treatment for liver metastases. Liver resection is the gold standard treatment for liver metastases in rectal cancer patients since the best oncologic outcomes are achieved with the R 0 -resection of metastatic disease. 35 Thus, resectability should be cautiously assessed before and during the surgical procedure to avoid futile liver surgery. It is extremely difficult to analyze the impact of surgical margin status on oncologic outcomes in liver resection for liver metastases of rectal cancer because of the independent variables such as systemic therapy, tumor burden, and genetic mutations. [217][218][219][220][221] Nevertheless, best oncologic outcomes are achieved with R 0 -resection, and therefore, it should always be the aim of surgical treatment. However, it should also be emphasized that the risk of R 1resection should not preclude liver resection.
Both the definition of R 0 -resection and the optimal width of surgical margin are still a matter of debate. 222 In a recent meta-analysis of 34 retrospective studies, the oncologic outcomes were found to be superior with ≥10 mm clear surgical margins when compared to those with <10 mm. 223 However, there are also numerous studies reporting that there is no significant difference in oncologic outcomes with any width of clear surgical margins. 224-228 According to current evidence, achieving a clear surgical margin of ≥10 mm should be the aim, but ≥1 mm can be accepted to be adequate.
When the tumor is exposed during resection, we recommend extending the resection margins. [227][228][229] The influence of the utilization of the frozen section of the specimen and re-resection to obtain clear margins when the frozen section reveals R 1 -resection on oncologic outcomes is unclear. [229][230] Thus, it is up to the surgeon's discretion to perform a frozen section procedure. It can be impossible to get clear surgical margins in tumors adherent to major vascular structures that cannot be sacrificed. Such tumors can be removed by separating them from the vessel, which is called a "vascular" R 1 -resection. Several studies reported that the oncologic outcomes of vascular R 1 -resection are similar to that of R 0 -resection. 231

Surgical Technique for Liver Metastases of Rectal Cancer
Parenchyma-sparing and anatomic resections have similar oncologic outcomes, and therefore, parenchymasparing (non-anatomic, irregular, and atypical) liver resections should be preferred over anatomic resections in liver metastases, if possible. [232][233][234] The studies comparing the surgical and oncologic outcomes of open and minimally invasive liver resections failed to show any statistical difference. [235][236][237][238] Although minimally invasive procedures have some advantages, such as enhanced recovery and reduced blood loss, they demand a high level of experience and technical skill.
In fact, so-called "liver-first" approach is usually not a "true" liver-first because liver surgery is performed after systemic treatment, and it is indeed a "chemo-first" approach. We suggest that up-front liver resection or "true" liver-first approach may be an option in patients with solitary, small (≤3 cm) metastases if the metastasis is likely to disappear during or after systemic therapy and can be resected easily with low morbidity. Optimal surgical sequencing is yet to be defined; however, liver-first, primary-first, and simultaneous resection after systemic treatment have similar oncologic outcomes, and therefore, each approach may be considered in individualized treatment protocols. 239 Owing to high morbidity and mortality rates, we recommend considering a staged procedure if a major liver resection is required. 240 Otherwise, simultaneous resection may be a viable option.
In the United States, systemic therapy is considered the initial step in the management of patients with metastatic rectal cancer regardless of resectability. 59 In contrast, the guidelines of some European and Eastern countries recommend up-front surgery for metastatic rectal cancer if the primary and metastases are apparently resectable. 35, 216 Since there is yet no high-level evidence to support any of these approaches, both up-front surgery (primary-first, liver-first, or simultaneous resection) and systemic therapy may be the initial step in the management of rectal cancer patients with liver metastases if the whole tumor burden is clearly resectable.
There is yet no randomized study comparing surgical resection with other locoregional therapies in resectable liver metastases of rectal cancer. Since liver resection is currently considered the gold standard treatment, nonsurgical locoregional therapies should be used as an alternative to surgery or can be combined with surgery only in individualized treatment protocols.
Patients with a solitary, small (≤2 cm), centrally located metastasis that can safely be removed only by major liver resection, particularly with right hepatectomy, may be treated by ablative procedures. In addition, surgical resection can be combined with ablative procedures in patients with multiple, bilobar metastases in whom there are concerns about the quality and quantity of future liver remnant to clear the liver from all macroscopic lesions. Systemic treatment has the potential to convert initially unresectable or borderline resectable metastases to resectable ones. Moreover, systemic therapy provides a clear survival advantage even in patients in whom resectability cannot be achieved by any means. The next step after systemic therapy should be determined up to the objective response. Patients with chemo-sensitive tumors should be re-evaluated for resectability. Otherwise, it is advised to continue with second-line chemotherapy. 35,59,216

Technical Maneuvers to Enhance Resectability in Rectal Cancer Patients with Synchronous Liver Metastases
Even if an objective response to systemic therapy is achieved, initially potentially resectable and unresectable liver metastases may not be converted to resectable metastases. As mentioned above, the obstacle to resectability can be either low likelihood of achieving R 0resection or inadequate future liver remnant or both. In this setting, certain technical maneuvers are currently available to increase or provide resectability. Selective internal radiotherapy (SIRT) and ablative procedures can shrink or destroy the tumors and thereby increase the resectability rates. Moreover, SIRT has been shown to induce contralateral liver hypertrophy, if not as much as portal vein occlusion (PVO) does. 241 If the concern is the sufficiency of the future liver remnant, then PVO is the best option. 242

Timing of Liver Resection
Some authors suggested that disease progression should not be considered an absolute contraindication for liver resection unless liver metastases have become unresectable. 246 This may particularly be true for patients whose metastatic tumors remain stable after systemic therapy has been completed. Perioperative chemotherapy may increase DFS but has no impact on OS with the exception of chemo-naive patients. 59,247 Radiologic and metabolic response to chemotherapy may not correlate with pathologic response in liver metastases. 248

Management of Oligometastatic and Polymetastatic Rectal Cancer
While up-front surgery in patients who have resectable lung or liver metastasis can be performed, it is widely accepted that the initial step in the management of such patients should be the control of systemic disease with chemotherapy. It is generally preferred to perform staged procedures because of the high morbidity and mortality rates associated with multiorgan resections; however, simultaneous resection may also be an option in a highly selected subgroup of patients. 35,59,216 Surgery for rectal primary tumor should be avoided as much as possible unless there is an obstruction or perforation. In those patients with nearly obstructing lesions, short-course RT or insertion of stents may allow avoiding surgery. If these approaches do not result in palliation of the symptoms or prevent complete bowel obstruction, a diverting stoma or palliative resection can be performed.

Management of Isolated Lung Metastases
Overall, the 5-year survival rate has been reported to reach nearly 70% in patients with pulmonary metastases undergoing metastasectomy. 252 In patients with recurrent isolated pulmonary metastases, repeated resections can be offered selectively to improve long-term survival. 253 The presence of synchronous or metachronous liver metastases is not a contraindication for pulmonary metastasectomy if complete resection of all sites of disease is possible. Surgical resection may result in significant survival advantage in rectal cancer patients with isolated synchronous, metachronous, or recurrent resectable lung metastases. [254][255][256][257] The logic behind the management of isolated lung metastases should be similar to isolated liver metastases.

STANDARDS FOR THE TREATMENT OF LOCO-REGIONAL RECURRENCES
The gold standard treatment to obtain the longest survival for patients with loco-regional recurrence is R0 surgical resection. The presence of multiple distant metastases, local resectability, and prior treatment modality are the factors that can be considered in the management of loco-regional recurrence of rectal cancer. 258 The NCCN guideline recommends surgery for isolated pelvic and anastomotic recurrences and chemo and/or RT for unresectable disease. Debulking is not an option for recurrent rectal cancer. 35,59 Optimal interval is between 8 and 12 weeks between resection of the primary and metastatic lesion. The resectability of metastatic lesions should be evaluated every 2 months. 259,260 Management strategies should be calibrated under the supervision of an MDTB for the management of locoregional recurrences with radical surgery and hyperthermic intraabdominal chemotherapy. Feasibility of an R0 resection, benefit of up-front chemo-radio treatment, and use of ablation for distant metastases which are not candidates for resection are the denominators of radical surgery for local recurrences. 258,261 While distant organ metastases, paraaortic and supradiaphragmatic involved lymph nodes, S1-S2 invasion are the relative contraindications for pelvic exenteration, lumbar vertebral invasion and being unfit for major surgery are the exact contraindications.

Choice of Chemotherapy in Patients with Nonresectable Disease
Oxaliplatin-based (FOLFOX and XELOX) or irinotecanbased chemotherapies (FOLFIRI) or triplet combination (FOLFOXIRI) are used as first-and second-line therapies.
The best way to combine and sequence these agents is still not established. The choice of regimen depends on prior exposure to chemotherapy, comorbidities of the patient, and the patient's and the physician's choice. Access to all active agents is more important than a particular treatment sequence of specific regimens. Each chemo thera py/bi ologi c treatment line is associated with longer survival. 273,274 Regorafenib and trifl uridi ne-ti pirac il (TAS-102) are used in the treatment of patients with metastatic CRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and biologic agents.

Duration of Preoperative Chemotherapy
The risk of chemotherapy-related liver toxicities depends on duration of preoperative therapy and the interval between last chemotherapy and surgery. 275,276 Limiting preoperative chemotherapy to 8 cycles (16 weeks) decreases the risk of chemo thera py-as socia ted liver injury and avoids postoperative complications without any decrease in pathologic response rate. 4 If the interval between the last chemotherapy and resection is 4 or fewer weeks, the patients are more likely predisposed to postsurgical complications. 276

Choice of Biological Agent
There are several selection criteria for the biological agents: biomarker analysis, location of the primary tumor, intent of the therapy (curative vs palliative), and co-morbidities of the patient. The biological agents used in metastatic CRC targets are either angiogenesis or the EGFR.

The agents targeting angiogenesis pathway are bevacizumab, aflibercept, and regorafenib. Bevacizumab is the only antiangiogenic agent approved in first-line treatment. Aflibercept can be used in second-line treatment in combination with FOLFIRI. Regorafenib can be used after second-line treatment in patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) agent, and anti-EGFR therapy (if RAS wild type). Two monoclonal antibodies targeting the EGFR are cetuximab and panitumumab.
Cetuximab and panitumumab are only effective in the patients whose tumors have wild-type RAS (NRAS, KRAS) oncogene. In addition to the RAS mutational status, the location of the primary tumor is another factor influencing the efficacy of anti-EGFR agents. 277 In left-sided CRC, as in rectal cancer, without RAS and BRAF mutation, an anti-EGFR-containing regimen is preferred as a firstline treatment, because OS is superior with anti-EGFRcontaining regimens when compared with bevac izuma b-con taini ng regimens (med. OS 39 mo vs 33 mo). 277 If FOLFOXIRI is chosen for first-line therapy, bevacizumab or anti-EGFR therapies (cetuximab or panitumumab) can be combined with chemotherapy depending on the RAS and BRAF status. [278][279][280][281] FOLFOXIRI and bevacizumab combination is associated with a significant overall response rate, leading to a probability of surgical conversion of distant metastases approaching 40%, with 28% of patients having an R0 resection. 279 Similarly, 2 phase II trials combining either cetuximab or panitumumab with FOLFOXIRI showed high response rates, high probability of conversion rates, and R0 resection in RAS-wild and BRAF-wild patients. 280,282 In tumors with BRAF V600E mutation and wild-type RAS, response to anti-EGFR agents is unlikely. 268

Is There a Role of Using Biological Agents in Up-Front Resectable Patients?
Combining bevacizumab with chemotherapy in patients with up-front resectable CRC results in marginal benefits and risk of major complications. 284 Addition of anti-EGFR agents to up-front FOLFOX, even in RAS wild-type patients, results in worse progression-free survival. 285 We do not recommend use of bevacizumab or anti-EGFR agents in this setting.

Benefit of Postresection Adjuvant Therapy
Adjuvant systemic chemotherapy is usually recommended in patients who have undergone metastasectomy of hepatic and/or pulmonary metastases, although there is not enough evidence from clinical trials demonstrating a survival benefit. 286,287 The most commonly preferred regimen is a oxaliplatin-based chemotherapy regimen like FOLFOX.
In patients with up-front resectable metastases, the addition of bevacizumab or cetuximab to an oxaliplatinbased chemotherapy regimen is not recommended after resection of hepatic or pulmonary metastases. In patients with potentially resectable metastatic CRC, the addition of a biologic agent can be planned in the perioperative setting. 288

Role of Immunotherapy in Rectal Cancer
The benefit of immunotherapy with PD-1 inhibitors is limited to the subset of tumors with high levels of MSI-H/ dMMR. Tumors with MSI-H or with MMR genes are susceptible to immune checkpoint inhibitors. Pembrolizumab and nivolumab are 2 immune checkpoint inhibitors that have been shown to be effective in patients with MSI-H or dMMR metastatic CRC that has progressed following conventional chemotherapies. 289,290 The percentage of MSI-H/dMMR stage IV colorectal tumors ranges between 3.5% and 6.5%. [291][292][293] Incidence of MSI-H/dMMR tumors is the lowest in rectal cancers when compared with the other parts of the colon. 292

Preoperative or Adjuvant Radiotherapy for Metastatic Rectum Cancer
Kim et al 294 performed a propensity score-matched analysis and meta-analysis of published literature of patients with stage IV rectal cancer who underwent TME between August 2001 and December 2011 to evaluate the impact of RT on oncologic outcomes. Two groups of 39 patients each were stratified based on patients receiving adjuvant pelvic RT (RT group) and those who did not (non-RT group) using their propensity scores. The local recurrence-free survival (LRFS) of the RT group was significantly higher than that of the non-RT group (2-year LRFS: 100% vs 83.6%, respectively, P = .038), while the overall DFA and distant metastasis-free survival rates were similar for both groups; adjuvant pelvic RT was highlighted to improve loco-regional control in patients with stage IV rectal cancer eligible for TME. 294 As the phase-III trial (CAO/ARO/AIO-94) for 4 non-stage patients by Sauer et al 79 encouraged the preop erati ve/ne oadju vant CRT approach in comparison to postoperative CRT due to improved local control, acute, and long-term side effects, the neoadjuvant approach also in metastatic patients sounds reasonable. Agas et al 295  These results confirmed that preoperative HDR BT either alone or in combination with CRT may result in a better pCR but not necessarily translate into a better survival in comparison to outcomes with preoperative CRT. 298 When HDR BT was combined with CRT, the HDR BT was either delivered as 5 Gy or 10 Gy in 1 fraction or as 10 Gy in 2 fractions. Brachytherapy was prescribed at 10 mm from the applicator surface. When HDR BT was prescribed alone, usually 26 Gy delivered in 4 fractions was the most preferred dose to the clinical target volume defined as GTV and intra-mesorectal extension seen on MRI. 298 Overall, HDR BT is not recommended in routine practice but could be evaluated for selected patients.

Palliative Radiotherapy Indications
Locally advanced and recurrent rectal cancers frequently cause pelvic morbidity including pain, bleeding, and mass effect. 303 Palliative pelvic RT is used to relieve these symptoms and delay local progression. There is no established optimal RT regimen, and clinical practices vary at treating institutions' disposal. Overall, the symptom response rate to palliative RT in the retrospective series was 75%, and reported palliation rates were 78% for pain, 81% for bleeding and discharge, 71% for mass effect, and 72% for other pelvic symptoms. Therefore, palliative pelvic RT for symptomatic rectal cancer appears to provide relief for a variety of pelvic symptoms, although there is no documented optimal RT regimen in this context. 303

Is There a Role of Stereotactic Body Radiotherapy or Stereotactic Ablative Radiotherapy for Metastases?
Takeda et al 304 reported Japanese experience on the treatment outcomes of 21 patients (12 liver and 9 lungs) with 28 oligometastases from CRC treated by stereotactic ablative radiotherapy (SABR) using a risk-adapted regimen, from August 2011 to January 2015; a total dose of 50-60 Gy in 5 fractions was prescribed to the planning target volume. Along with the median follow-up duration of 27.5 months (range: 6.5-43.3 months), the local control rates at 1 and 2 years from the start of SABR were 100% without any severe toxicities (≥grade 3), while the DFS and actuarial OS rates were 62% and 55%, and 79% and 79%, respectively. 304 Will Jin et al 305

Radiofrequency and Microwave Ablation
Patients with a limited number of lesions and involved sites should be considered as having oligometastatic disease. The primary goal for patients who present with technically resectable liver metastases is R0 resection. In these patients, the additional use of local ablation therapies such as radiofrequency ablation (RFA) has been shown to be feasible. The selection of the best technique from the list of ablative therapies for use in this setting differs according to the size and localization of the metastases, the rates of local control achieved (with the local control greater for surgery than for the other options), the invasiveness of the technique, the non-tumor-related prognostic considerations and patient factors, as well as patient preferences, the local expertise regarding the ablative methods, and consideration of patient frailty and life expectancy. 309 A treatment goal for patients with metastatic CRC involves an attempt to eradicate all visible metastatic lesions using the best instrument from the toolbox of local ablative therapies, in combination with systemic therapy. 309 The overall goal of this strategy is not necessarily to cure the patient, as the prognosis for these patients is generally poor due to the unfavorable localization of their metastases and the number of involved organs coupled with the limitations of local ablative treatments, compared with surgical resection. The CLOCC trial, a randomized phase-II trial with a median followup of 9.7 years, has demonstrated that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases. 310 In patients with advanced metastatic CRC, thermal ablation such as RFA often cannot be used due to the inherent size limitation of ∼3 cm. However, in the phase-II CLOCC trial (chemotherapy plus or minus RFA), RFA combined with surgical resection for the treatment of patients with CRC liver metastases suggested an improvement in both PFS and OS. A considerable amount of data are available on the use of thermal ablation in combination with liver resection for the treatment of patients with CRC liver metastases.

Radioembolization or Chemoembolization
To date, the data on chemoembolization for liver metastases from CRC are mostly observational series in various treatment situations. [311][312][313] Comparative data are limited to irinotecan-based drug-eluting beads in a small phase-II cohort in previously treated patients showing a benefit vs systemic chemotherapy, 314 and the role of intra-arterial irinotecan in patients pre-exposed to IV irinotecan is unclear. 309 Radioembolization involves a single delivery of yttrium-90 connected to either resin or glass particles into the hepatic artery with the therapeutic effect essentially limited to irradiation. For patients with liver-limited metastases failing the available chemotherapeutic options, radioembolization with yttrium-90 resin microspheres has been shown to prolong the time to tumor progression in the liver, based on a small randomized phase-III study. 315 For patients with liver-limited disease failing the available chemotherapeutic options, radioembolization with yttrium-90 microspheres should be considered. If radioembolization is not possible for any reason, chemoembolization may be also considered a treatment option.

Can Radioembolization Be Used as a Salvage Therapy in Patients with Liver Metastasis?
The use of radioembolization with resin microspheres has demonstrated improved results in the third-line or chemorefractory disease in patients with liver-dominant metastatic disease. 3 The SIRFLOX and FOXFIRE studies failed to show improved OS with the combinational use of radioembolization (resin microspheres) with systemic chemotherapy compared to chemotherapy alone in the first-line treatment of patients with metastatic CRC with unresectable liver metastases. 316

Can Radioembolization Be Used for Downstaging of Liver Metastases?
The evidence for downstaging of metastatic liver disease with radioembolization is limited to a few case reports and small case series and 1 small clinical trial. 317 Justinger et al 318 reported 13 CRC patients with marginally resectable liver metastasis who were treated with resin microspheres for intended downstaging. 318 Hepatic resection was performed in 11/13 patients after a median of 57 days (range: 39-153) following radioembolization, combined with associating liver partition and portal vein ligation for staged hepatectomy in 7/11 and with portal vein embolization in 1/11.

Colorectal Cancer Screening and Surveillance
Characteristics of a successful CRC screening program should include effective identification of individuals eligible for screening, determination of a consistent screening strategy in the national setting, initiation of screening at the appropriate age, applicability and accessibility of screening tools, and follow-up of performance measures to ensure high-quality screening in the population. Colorectal cancer screening parameters include identification of eligible individuals, consistency of screening strategy at the national level, appli cabil ity/a ccess ibili ty of screening tools, and performance measures. The performance of the screening program should be followed up and reported by the local and national regulatory authorities to ensure a high-quality screening process at the level of physicians and screening centers. 319 Evidence-based quality indicators for a colonoscopy screening are as follows: The adenoma detection rate should be ≥25% overall or ≥30% for male patients and ≥20% for female patients. Cecal intubation rate should be ≥95%. 319,320 Split-dosing of bowel preparations should be used to ensure effective cleansing of the colon before the colonoscopy procedure. The split-dose regimen is recommended because effective bowel preparation requires at least half the preparation to be ingested on the day of the colonoscopy. 321 The National CRC Screening Program was initiated formally by the Ministry of Health in Turkey on September 1, 2014. According to the national screening program, it is recommended to offer a fecal occult blood test (FOBT) every 2 years for every individual starting at the age of 50. Regardless of the initial FOBT result, the program mandates colonoscopy at the age of 51 and a follow-up colonoscopy 10 years after the initial negative colonoscopy. Colorectal cancer screening protocols are highly variable around the world. While programmed screening is common among European countries, opportunistic screening using colonoscopy is the main strategy in the United States. In many European countries, including United Kingdom, screening is provided by primary care physicians using fecal immunochemical test (FIT) or FOBT. In several countries including Germany and Italy, colonoscopy is the preferred initial screening tool. The United States Preventive Services Task Force (USPSTF) guideline 322 does not give preference for any single screening test over one another and advises that patients should be offered a choice among screening modalities including stool-based tests or direct colon visualization techniques. The stool-based test includes annual FOBT, annual FIT, or FIT-stool DNA every 1-3 years, while direct visualization techniques include flexible sigmoidoscopy alone (every 5 years), or combined (every 10 years), with the annual FIT; colonoscopy (every 10 years); and CT colonography (every 5 years). The Multi-Society Task Force of Colorectal Cancer, composed of the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, issued updated CRC screening guidelines in 2017. 319 This multi-society guideline categorizes screening tests into 3 tiers. The most highly recommended is the first-tier which includes colonoscopy every 10 years or annual FIT. Second-tier includes CTC every 5 years, FIT-stool DNA every 3 years, and flexible sigmoidoscopy every 5-10 years. Third-tier is capsule colonoscopy every 5 years. The optimal screening method for CRC is colonoscopy; however, considering the limited financial resources and shortage in the number of endoscopists, annual FIT/FOBT should be incorporated as the main screening tool in the primary care setting. Nevertheless, primary care physicians should refer all individuals for colonoscopy starting at the age of 50 regardless of the FIT/FOBT result.
The international guidelines recommend a repeat colonoscopy after 3 years if index colonoscopy reveals a highrisk polyp (>3 adenomas or sessile serrated polyps, villous component, high-grade dysplasia or intramucosal cancer, any polyp ≥10 mm). Individuals with high-risk features (personal or family history of CRC, inflammatory bowel disease, and hereditary cancer syndromes) require earlier initiation of screening with shorter interval; however, details of screening algorithm in high-risk individuals are beyond the scope of this consensus report. The National CRC Screening Program algorithm is appropriate and recommendations from the USPSTF 2012 guideline, which can be summarized as 3-5-10 years intervals for colonoscopy according to the result of index colonoscopy, should be implemented into the current screening program.

What Is the Optimal Age Interval for CRC Screening?
Most of the societies, except the American Cancer Society (ACS), recommend initiating CRC screening at the age of 50 in all individuals with average risk. The ACS updated its guidelines for screening people at average risk for CRC at age 45 years and above. The rationale for a younger starting age for screening is the apparent increased incidence of CRC in younger adults. 323 Both USPSTF and ACS guidelines recommend continuing screening up to age 75 years if screening is up-to-date. If screening is not up-to-date, they consider screening up to age 85 years. It is recommended to discontinue screening in patients over 85 years of age and patients with a shortened life expectancy which is defined as less than 10 years of remaining life.

Which of the Imaging Technic and Screening Method Is Cost-Effective?
Brachytherapy and CEA follow-ups were found to be more cost-effective. 324 Contrast-enhanced MRI seems to be more cost-effective for detecting metastases that are undetectable with other imaging techniques for deciding treatment to curative intent for patients who are scheduled to undergo liver resection. Magnetic resonance imaging has also been found more precise in early and correct diagnosis. 325 We recommend performing CEA every 3-6 months in first 2 years and then every 6 months for a total of 5 years.
We recommend performing thoraco-abdominal CT as per the following duration:  326 Thus, advantages of the neoadjuvant approach include better local control (even in the setting of optimal TME, an increased likelihood of sphincter-saving surgery, a lower risk of posttreatment bowel dysfunction (soiling and frequent stooling) and a lower risk of chronic anastomotic stricture. Also, preoperative RT can avoid the occurrence of RT-induced injury to the small bowel trapped in the pelvis by postsurgical adhesions. 134 All therapeutic options for rectal cancer, namely surgery, chemotherapy, and radiation therapy, adversely affect fertility. Discussions about fertility risks associated with CRC treatment occur infrequently (34%) among young adults with newly diagnosed CRC. 327 However, it has been shown that great majority of younger cancer survivors see their cancer experience as potentially making them better parents. Those without children may want to have children in the future. 328 A study among younger male cancer survivors showed positive emotional effects in cancer therapies when they are offered banking sperm even if it will never be used. 329 Thus, in rectal cancer fertile patients in whom surgery, chemotherapy, and RT are planned, fertility risks should be counseled and options to protect fertility should be offered. These options include oocytes and embryo cryopreservation, ovarian transposition and ovarian suppression in females, and cryopreservation "bank" sperm in males.
Although there is no data on preoperative assessment of preoperative sphincteric functions in rectal cancer patients who do not demonstrate signs of incontinence and/or pudendal neuropathy, a study has shown that RT can cause significant prolongation of pudendal nerve terminal motor latency (PNTML). 330  Hereditary CRC has 2 well-described forms: 1. Polyposis (including familial adenomatous polyposis (FAP) and attenuated FAP (AFAP), which are caused by pathogenic variants in the APC gene, and MUTYHassociated polyposis, which is caused by pathogenic variants in the MUTYH gene, and 2. LS (often referred to as hereditary nonpolyposis colorectal cancer), which is caused by germline pathogenic variants in DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM.
Many of these syndromes are also associated with extracolonic cancers and other manifestations. Serrated polyposis syndrome, which is characterized by the appearance of hyperplastic polyps, appears to have a familial component, but the genetic basis remains unknown. The natural history of some of these syndromes is still being described. Many other families exhibit aggregation of CRC and/or adenomas but with no apparent association with an identifiable hereditary syndrome and are known collectively as familial CRC. In addition, most individuals with CRC diagnosed before 50 years of age and without a family history of cancer do not have a pathogenic variant associated with an inherited cancer syndrome.